This research program is focused on characterizing the genetic interactions that mediate fatal disease in the lupus-prone NZM2410 mouse model of SLE. During the current funding period of this MERIT award, we have focused on identifying the genetic interactions among individual loci within the Sle1 cluster that are responsible for the development of fatal disease. We have also characterized a series of four suppressive modifiers of disease derived from the NZW genome. Finally, we have extended our analyes of these susceptibility loci into human SLE patient populations via collaboration with John Harley and colleagues at the Oklahoma Medical Research Foundation. These studies have been highly productive during the first 3.5 years of funding and have supported 6 publications, three of these in high-profile journals. Most notably, we have fine mapped the potent Slesl suppressive modifier into a -450 Kb genomic interval and are poised to identify the causative suppressive allele using BAGtransgenic rescue strategies. In addition, we have obtained strong data indicating that two specific genes within the SLAM/CD2 gene family are resonsible for autoimmunity in both our murine models and human European American and Hispanic SLE patients. We are proposing to continue these investigations during the extension of the MERIT award and to develop two additional specific aims. These are: Aim 1) To identify the gene or genes within the Sle1 gene cluster that interacts with Slelb and Tlr7 to mediate fatal disease. We recently identified the genetic lesion underlying the potent autoimmune accelerating y chromosome locus (yaa) as a translocated TLR7 gene. We have also obtained evidence that the interactions of this dysregulated TLR7 gene involve both the SLAM/CD2 gene family and at least one additional gene within a 4 mBase genomic segment adjacent to the SLAM/CD2 locus. We are proposing to fine map and identify this additional locus. Aim 2) To identify novel new suppressive modifiers of fatal disease mediated by Slelyaa. These studies will utilize wild-derived inbred strains as a source of novel new suppressive modifiers of the fatal systemic autoimmunity produced by the combination of Sle1 and yaa. The goal of this analysis will be to identify suppressive modifiers by linkage analysis and capture them in congenic intervals on the B6.Sle1 strain. The long term goal of these studies is to identify novel therapeutic targets for the modulation of systemic autoimmunity.